EP0076066A1 - Penicillin-Derivate - Google Patents

Penicillin-Derivate Download PDF

Info

Publication number
EP0076066A1
EP0076066A1 EP82304892A EP82304892A EP0076066A1 EP 0076066 A1 EP0076066 A1 EP 0076066A1 EP 82304892 A EP82304892 A EP 82304892A EP 82304892 A EP82304892 A EP 82304892A EP 0076066 A1 EP0076066 A1 EP 0076066A1
Authority
EP
European Patent Office
Prior art keywords
compound
hours
general formula
acid
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP82304892A
Other languages
English (en)
French (fr)
Other versions
EP0076066B1 (de
Inventor
Shigeaki Muto
Kouichi Niimura
Takao Ando
Akihiko Kanno
Takao Furusho
Chikao Yoshikumi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kureha Corp
Original Assignee
Kureha Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP56149870A external-priority patent/JPS5852292A/ja
Priority claimed from JP56149869A external-priority patent/JPS5852291A/ja
Application filed by Kureha Corp filed Critical Kureha Corp
Publication of EP0076066A1 publication Critical patent/EP0076066A1/de
Application granted granted Critical
Publication of EP0076066B1 publication Critical patent/EP0076066B1/de
Expired legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group

Definitions

  • the present invention relates to penicillin derivatives, their preparation and pharmaceutical compositions containing them.
  • Penicillins are well known as excellent antibiotics due to their selective toxicity to bacteria.
  • the penicillin antibiotic has a serious defect, that is it may disturb the beneficial bacterial colonies ordinarily present in living bodies, particularly the intestinal bacterial colonies, since it may be also antibacterially active against the beneficial bacteria. This defect is very serious when such an antibiotic is orally administered.
  • "microbisme selectionne et substitue” is caused resulting in colitis and diarrhoea.
  • the present invention is concerned with antibiotics without this defect. More particularly, the present invention relates to compounds obtained by chemically modifying a penicillin, antibacterial activity being lost by such chemical modification but recovered when the compound is absorbed into a living body.
  • the compounds of the invention can be formulated into pharmaceutical compositions to provide a medicine exhibiting antibacterial activity similar to a penicillin antibiotic in a living body.
  • Compounds of the present invention (hereinafter referred to as the present compound) have the general formula (I): wherein R 1 is or and wherein R 4 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a physiologically acceptable cation, preferably an alkali metal cation.
  • the present compound may therefore be in the form of a salt other than an alkali metal salt, for example an alkali earth metal salt, an aluminium salt or an amnonium salt.
  • the present compound, and indeed all penicillin derivatives described and illustrated by formulae herein, have the usual absolute stereochemistry of penicillins of 3S:5R:6R.
  • the present compound is derived from a penicillin antibiotic by a chemical modification. It is absorbed into a living body without affecting the bacterial colonies ordinarily present in living bodies and shows an antibacterial activity only when entering into blood, therefore, the present compound is an antibiotic of the new type quite different from the conventional penicillin antibiotics.
  • the present compound may be synthesized by the following processes.
  • the present compound has low toxicity and exhibits an antibacterial activity in a living body without affecting the intestinal Jacterial colonies.
  • the present compound can be useful in the same field as the conventional penicillin antibiotics since the present compound is transformed into a penicillin antibiotic in a living body.
  • the present compound can be used in a dosage unit form such as a drug or a pharmaceutical composition.
  • the composition may contain 0.01 to 99.5% by weight, generally 0.1 to 90% by weight of the present compound as an active ingredient.
  • the pharmaceutical composition contains a pharmaceutically acceptable carrier, diluent or adjuvant as well as at least one of the present compound.
  • the composition may contain filler, extender, binder, wetting agent, disintegrant, retarder of dissolution, accelerator of reabsorption, adhesive carrier and/or lubricant, for example, starch, mannitol, silicic acid, cellulose derivative, gelatin, alginate, glycerol, agar, calcium carbonate, sodium hydrogen carbonate, paraffin, quartarnary ammonium compound, glycerol monostearate, kaolin, bentonite, talc, aluminum stearate, magnesium stearate, polyethylene glycol and the like.
  • the pharmaceutical composition may be administered orally or rectally or by injection.
  • the dosage form for oral administration may be tablet, capsule, powder, granule, pill, ampoule or the like.
  • the composition may be in the form of pharmaceutically acceptable emulsion, solution, suspension and the like.
  • a syrup or elixir may contain an inert diluent such as water and paraffin and may be used as a liquid composition suitable for oral administration. These composition may contain an adjuvant such as wetting agent, edulcorant and seasoning agent.
  • a suppository containing the present compound as an active ingredient may contain polyethylene glycol and/or fatty acid or ester thereof.
  • the pharmaceutical composition for injection may be a stearilized aqueous or nonaqueous solution, suspension or emulsion and may contain, for example, propylene glycol, polyethylene glycol, olive oil and the like.
  • the present compound may be useful for the same as the conventional penicillin antibiotics and effective in treating an infectious disease due to bacteria such as Streptococcus, Pneumococcus, Gonococcus, diphteria bacillus, Staphylococcus, Spirochaeta, Actinomyces, Shigella, E. coli, Myxomycetes, Enterecoccus, Meningococcus and the like.
  • bacteria such as Streptococcus, Pneumococcus, Gonococcus, diphteria bacillus, Staphylococcus, Spirochaeta, Actinomyces, Shigella, E. coli, Myxomycetes, Enterecoccus, Meningococcus and the like.
  • the diseases to be able to be treated with the present compound is exemplified as follows; tonsilitis, pharyngitis, laryngitis, wound, burn, postoperative secondary infection, lymphadenitis, septicemia, bacterial endocarditis, pneumonia, pulmonary suppuration, bronchitis, scarlet fever, gonorrhea, cystitis, pyothorax, urethritis, bacterial dysentery, meningitis, diphtheria, otitis media, carbuncle, actinomycosis and the like.
  • the dose of the drug or the pharmaceutical composition of the present compound may depend on the degree of the infection and the condition of the patient, and generally the dose of 0.1 to 10 g may be administered to an adult patient per one day, divided into several times.
  • the filtrate was subjected to distillation to evaporate off the solvent thereof, and the residue was mixed with 100 ml of water and the pH of the mixture was adjusted to 2 by the addition of aqueous 5% solution of hydrochloric acid.
  • the thus separated solid material was extracted with 200 ml of ethyl acetate, washed three times with water and dried on anhydrous magnesium sulfate. Then the solvent was distilled off from the dried extract.
  • Example 9 In the same manner as that in Example 9 except for using 378 mg of chloromethyl ethyl ether instead of 500 mg of chloromethyl methyl ether in Example 9, 680 mg of a crude product was obtained. Recrystallizing from a mixed solvent of ethyl acetate and n-hexane, 571 mg of the purified product was obtained with a yield of 70%.
  • Acute toxicity of the present compounds were determined as follows.
  • Each of the present compounds was dispersed in a physiological saline solution.
  • the dispersion was administered to an ICR-JCL mouse orally by a stomach sonde or intraperitoneally by injection at a predetermined amount.
  • LD 50 value was obtained from the cumulative mortality of the treated mice by applying the data to the Litchfield-Wilcoxon's graphical method. All of the present compounds gave LD SO value of more than 10 g/kg in both oral and intraperitoneal administrations.
  • the LD 50 value of the conventional penicillin as a comparative antibiotic is about 5 g/kg.
  • mice one group consisting of five female ICR mice of 6-week-old
  • mice one group consisting of five female ICR mice of 6-week-old
  • feces of each mouse was collected and diluted with an anaerobic diluent (phosphoric buffer solution) of 100 times volume and ground. 0.1 ml of the diluted and ground feces was smeared on each culture medium shown in Table 1 and cultured aerobically or anaerobically (according to the anaerobic glove box method) under each condition shown in Table 1. The number of each bacterium shown in Table 1 was counted.
  • anaerobic diluent phosphoric buffer solution
  • Antibacterial activity of the present compounds was examined as follows.
  • Each bacterial strain was inoculated into the Mueller-Hinton's culture medium and cultured at 37°C for 18 to 48 hours.
  • the culture medium was diluted so as to contain 1 x 10 6 cells of the bacteria per one ml, and the obtained medium was used as the bacterial specimen.
  • Agar plates were prepared by adding one part by weight of each solution of the present compounds having a predetermined concentration to nine parts by weight of Mueller-Hinton's culture medium.
  • a loopful amount of the bacterial specimen prepared above was smeared to make a streak of about 2 cm on each agar plate and cultured at 37°C for 18 to 24 hours.
  • the minimum concentration for completely inhibiting proliferation of the bacteria (referred as MIC) was determined.
  • a rat liver homogenate (S-9, manufactured by Oriental Yeast Company, Japan) was used in the following composition per one ml (hereinafter referred to as S-9 mix).
  • S-9 mix a rat liver homogenate
  • 0.1 ml of each solution of the present compounds at a concentration of 100 ug/ml was mixed with 0.9 ml of S-9 mix or 0.9 ml of 0.1 M phosphoric buffer solution (as a control) and the obtained mixture was incubated at 37°C for 20 min with shaking.
  • Staphylococcus aureus IAM 1011 was inoculated into a Mueller-Hinton's culture medium and cultured at 37°C for 18 hours.
  • the culture medium was adjusted to a cell concentration of 1 x 10 8 per one ml and mixed with 50 times by volume of Mueller-Hinton's agar culture medium to obtain an agar plate.
  • a penicillin cup of 8 mm in diameter was placed on the agar plate prepared above, and into the cup 0.1 ml of the mixture was introduced and allowed to stand at 4°C for 2 hours and then cultured at 37°C for 18 hours to measure the diameter of a circle in which the proliferation of bacteria was inhibited (proliferation-inhibiting circle).
  • the results are shown in Table 4.
  • the proliferation-inhibiting index is shown with the ratio (%) of the diameter of the proliferation-inhibiting circle obtained by using each of the present compounds to that obtained by using the comparative compound(conventional penicillin antibiotic).
  • the antibacterial activity of the present compound is activated by an enzyme in a living body, although it itself shows a low antibacterial activity in the absence of an activating enzyme.
  • Escherichia coli IFO 12734 (1.4 x 10 8 ) was inoculated intraperitoneally to ddY-SPF mice (a group consisting of 20 mice). Just after and at 4 hours after the infection, each of the present compounds was administered orally at a dose of 500 mg/kg and the mortality of the mice due to the infection was observed for 7 days. More than 35% of the mice administered with the present compound survived even on the 7th day after the infection, while all mice without the administration with the present compound died on the 2nd day after infection.
  • the present compound and lactose was mixed and then an aqueous solution of hydroxypropylcellulose was admixed, and the mixture was kneaded, dried and pulverized. Then magnesium stearate dispersed previously into starch was admixed and the mixture was made into a tablet by the conventional method for tabletting.
  • the present compound, starch and lactose were mixed, and an aqueous solution of hydroxypropylcellulose was admixed and the mixture was dried and pulverized.
  • the pulverized material was sifted by 12 to 48 mesh sieves to obtain a granule.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP82304892A 1981-09-22 1982-09-16 Penicillin-Derivate Expired EP0076066B1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP56149870A JPS5852292A (ja) 1981-09-22 1981-09-22 抗生物質と医薬剤
JP56149869A JPS5852291A (ja) 1981-09-22 1981-09-22 ペニシリン系抗生物質誘導体とその医薬剤
JP149869/81 1981-09-22
JP149870/81 1981-09-22

Publications (2)

Publication Number Publication Date
EP0076066A1 true EP0076066A1 (de) 1983-04-06
EP0076066B1 EP0076066B1 (de) 1986-11-26

Family

ID=26479636

Family Applications (1)

Application Number Title Priority Date Filing Date
EP82304892A Expired EP0076066B1 (de) 1981-09-22 1982-09-16 Penicillin-Derivate

Country Status (4)

Country Link
US (1) US4540689A (de)
EP (1) EP0076066B1 (de)
AU (1) AU559689B2 (de)
DE (1) DE3274453D1 (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6632961B1 (en) * 1998-05-22 2003-10-14 Abbott Laboratories Antiangiogenic drug to treat cancer, arthritis and retinopathy
EP1138333B1 (de) * 1999-10-12 2004-02-25 Daiichi Suntory Pharma Co., Ltd. Arzneimittel zur oralen verabreichung
PA8579701A1 (es) * 2002-08-23 2005-05-24 Pfizer Prod Inc Profarmaco inhibidor de beta-lactamasa
BRPI0410936A (pt) * 2003-06-05 2006-06-27 Pfizer Prod Inc pró-fármaco inibidor da beta-lactamase

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB630264A (en) * 1945-12-20 1949-10-10 Merck & Co Inc Process for preparing esters of penicillin g
GB1081093A (en) * 1964-03-17 1967-08-31 Rech S Et D Applic Scient Et M Improvements in or relating to 6-[d(-)-alpha-(amino-phenylacetamido)]-penicillanic acid derivatives
DE1940571A1 (de) * 1968-08-08 1970-02-19 Pliva Pharm & Chem Works Neue Penicilline und Verfahren zu deren Herstellung
FR2085746A1 (de) * 1970-03-26 1971-12-31 Gallardo Antonio Sa
USB547208I5 (de) * 1972-12-08 1976-02-24

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US547208A (en) * 1895-10-01 Net tucker hall
FR2086746A5 (de) * 1970-04-07 1971-12-31 Alsthom
US4342768A (en) * 1979-10-22 1982-08-03 Pfizer Inc. Bis-esters of 1,1-alkanediols with 6-beta-hydroxymethylpenicillanic acid 1,1-dioxide and beta-lactam antibiotics
US4317775A (en) * 1980-01-07 1982-03-02 Hoffmann-La Roche Inc. Amoxicillin derivatives
IT1134541B (it) * 1980-12-02 1986-08-13 Juan Scalesciani Derivato della ammino-penicillina,processo per la sua preparazione e composizioni terapeutiche che lo comprendono come principio attivo

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB630264A (en) * 1945-12-20 1949-10-10 Merck & Co Inc Process for preparing esters of penicillin g
GB1081093A (en) * 1964-03-17 1967-08-31 Rech S Et D Applic Scient Et M Improvements in or relating to 6-[d(-)-alpha-(amino-phenylacetamido)]-penicillanic acid derivatives
DE1940571A1 (de) * 1968-08-08 1970-02-19 Pliva Pharm & Chem Works Neue Penicilline und Verfahren zu deren Herstellung
FR2085746A1 (de) * 1970-03-26 1971-12-31 Gallardo Antonio Sa
USB547208I5 (de) * 1972-12-08 1976-02-24

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE, no. 1, 1968, pages 420-4; *
JOURNAL OF THE CHEMICAL SOCIETY, 1965, part II, pages 1565-3016; *

Also Published As

Publication number Publication date
US4540689A (en) 1985-09-10
DE3274453D1 (en) 1987-01-15
AU559689B2 (en) 1987-03-19
EP0076066B1 (de) 1986-11-26
AU8847282A (en) 1983-04-14

Similar Documents

Publication Publication Date Title
CH617202A5 (de)
US4053360A (en) Enzymatic preparation of 6-D-(-)-α-amino-α-(p-hydroxyphenylacetamino)penicillin acid
AU2006300882B2 (en) Crystalline sodium salt of cephalosporin antibiotic
EP0076066A1 (de) Penicillin-Derivate
EP0075449B1 (de) Penicillin-Derivate
US4496561A (en) Cephalosporin derivative
EP0113242B1 (de) Cephalosporinderivate
EP0075450B1 (de) Cephalosporinderivate
EP0075451B1 (de) Cephalosporinderivate
AU600536B2 (en) Crystalline salts of {3s(z)}-2-{{{1-(2-amino-4-thiazolyl) -2-{{2,2-dimethyl-4-oxo-1-(sulfooxy)-3-azetidinyl}-amino-2- oxoethylidene}-amino}oxy}acetic acid
EP0075452B1 (de) Cephalosporinderivate
US4285939A (en) Cephalosporin derivatives, and antibacterial drugs containing the derivatives
EP0113243B1 (de) Cephalosporinverbindungen
US4446137A (en) Cephalosporin derivative and pharmaceutical composition containing the derivative
EP0113245B1 (de) Cephalosporinverbindungen
US4734409A (en) Cephalosporin derivative, process for producing the same and pharmaceutical composition containing the same
JP4730879B2 (ja) キガマイシノン類及びその製造方法、並びに、該キガマイシノン類を含む薬用組成物
Kobori et al. Synthesis and biological properties of 3-[(Z)-2-(1, 2, 3-thiadiazolyl) ethenyl]-substituted cephalosporins and related compounds: new oral cephalosporins
JPH0160010B2 (de)
FR2538393A1 (fr) Procede de preparation d'oxacephalosporines, nouveaux produits ainsi obtenus et compositions pharmaceutiques antibacteriennes les renfermant
CH640239A5 (en) Process for the preparation of novel cephem-4-carboxylic acid compounds
JPH0234357B2 (ja) Sefuarosuhorinjudotaioyobigaijudotaioganjusuruyakuzai
JPH0240071B2 (ja) Sefuarosuhorinjudotaioyobigaijudotaioganjusuruyakuzai
JPH021836B2 (de)

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): BE CH DE FR GB IT LI SE

17P Request for examination filed

Effective date: 19830924

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): BE CH DE FR GB IT LI SE

REF Corresponds to:

Ref document number: 3274453

Country of ref document: DE

Date of ref document: 19870115

ET Fr: translation filed
ITF It: translation for a ep patent filed

Owner name: SOCIETA' ITALIANA BREVETTI S.P.A.

RIN2 Information on inventor provided after grant (corrected)

Free format text: MUTO, SHIGEAKI * NIIMURA, KOUICHI * ANDO, TAKAO * KANNO, AKIHIKO * FURUSHO, TAKAO * YOSHIKUMI, CHIKAO

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19890908

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 19890929

Year of fee payment: 8

ITTA It: last paid annual fee
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 19900803

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19900917

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19900919

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19900925

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Effective date: 19900930

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19901031

Year of fee payment: 9

BERE Be: lapsed

Owner name: KUREHA KAGAKU KOGYO K.K.

Effective date: 19900930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19910916

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Effective date: 19910930

Ref country code: CH

Effective date: 19910930

GBPC Gb: european patent ceased through non-payment of renewal fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Effective date: 19920529

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19920602

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

EUG Se: european patent has lapsed

Ref document number: 82304892.1

Effective date: 19910527